Hepatic encephalopathy (HE), also called as portosystemic encephalopathy (PSE), refers to a reversible condition characterized by impaired brain function observed in patients with advanced liver disease. It can be observed in 30 to 45% of patients with cirrhosis. However, hepatic encephalopathy is not a single clinical manifestation. Edema, brain atrophy, reversible metabolic encephalopathy, or any combination of these diseases might be associated with hepatic encephalopathy.[1] Depending upon the severity, presence of symptoms, clinical and neuropsychiatric condition, HE can be categorized as minimal HE and clinically overt HE.[1] Minimal hepatic encephalopathy (MHE) is thus referred to as a subgroup of hepatic encephalopathy, which by definition is not clinically apparent. Although its precise prevalence is unknown, mild hepatic encephalopathy is seen in 80% of cirrhosis patients. The hallmarks of MHE include anomalies in central nervous system function, including substantial impairments in attention, psychomotor speed, visuospatial perception, response 2 inhibition, and delayed information processing.[2,3] Since the standard neurologic examination in cases of MHE is generally within normal limits, diagnosing MHE is challenging. Because MHE is a covert condition, neuropsychiatric testing is used to diagnose this condition.[4] Numerous neuropsychological tests, such as computerized tests like the essential flicker 3 frequency and inhibitory control tests, psychometric assessments, and electrophysiological investigations, have been created to identify MHE.[5] Introduced by Weissenborn et al[5], PHES includes five individual tests: the Digit Symbol Test (DST), Serial Dotting Test (SDT), Line Tracing Test (LTT), and the Number Connection Tests A and B (NCT-A and NCT-B). This test battery evaluates a range of cognitive functions that are often impaired in MHE, such as motor speed and accuracy, concentration, attention, visual perception, visual-spatial skills, visual construction abilities, and memory. PHES is straightforward to administer and culturally adaptable, making it practical for clinical use. An international panel of experts recommended the use of PHES as one of the better methods for detecting MHE.[6] PHES is a validated scale and according to a study conducted in India, sensitivity of PHES at the cut off of 5 or less was 65.7% whereas specificity was 100%.[7] The data regarding the role of PHES in MHE is scarce in central India. The present study was thus conducted at our study centre to assess the effectiveness of PHES in detecting minimal hepatic encephalopathy in liver cirrhosis patients.

The present study was conducted as a comparative cross-sectional observational study on patients with liver cirrhosis (radiologically proven based on USG findings) having no overt signs of Hepatic Encephalopathy and age and sex matched healthy controls at Department of Medicine, Gandhi Medical college and associated Hamidia Hospital Bhopal, during the study period of 18 months i.e. from 1st July 2023 to 31st December 2024. Sample size was estimated using the formula n = (z)2p(1–p)/d2 where; z=1.96 at 95% CI, p= prevalence of MHE= 22%[8] q=1-p=26% d= 10% allowable error Using the formula, sample size was estimated to be 66 and hence a total of 70 cases and 70 controls were included. All the cases with confirmed cirrhosis (based on USG) belonging to age range of more than 18 years and willing to participate in the study were included as cases whereas patients with history of overt hepatic encephalopathy, consumption of Psychoactive drugs/ Antibiotics during past 2 weeks or alcohol >50g/day within past 3 months, with Psychiatric/Neurological disorders, Hepatocellular Ca or Other malignancy, previous TIPS or shunt surgery based on USG findings were excluded. Exclusion criteria for controls was presence of psychiatric/neurological disorders, consumption of psychotropic drugs or alcohol of >50g/d within past 3 months and patients with CLD. Prior to this study, the due permission was obtained for using PHES scoring system. After obtaining ethical clearance from the Institute’s ethical committee, all the patients with liver cirrhosis satisfying inclusion criteria were enrolled and written consent was obtained from all of them. Age and sex matched healthy controls were selected and consent was obtained from controls. All the participants were subjected to detailed history taking as per the proforma. Further, detailed general and systemic examination was done and findings were documented. In addition, necessary investigations and EEG were done for all and findings were documented. To diagnose minimal hepatic encephalopathy, all the 5 tests included in PHES (validated and standardized for Indian population)[6] were conducted in sequence (DST, NTC-A, NTC-B, LTT, and SDT). PHES was done in quiet area after explaining the pattern of the test and using pencil. All the tests were done after the trial run. DST (digital symbol test) – The patient was shown a table where each number represents a distinct symbol and patient was instructed to complete an empty table with 80 digits by entering as many corresponding symbols as possible during 90 seconds. The number of correct corresponding symbols was the final score.[9] Number connection test A (NCT A) - the patient was instructed to connect the circles from 1 to 25 as quickly as possible without making any mistakes. If the patient makes a mistake, they have to pause, fix it, and then continue while the timer is still running. The time (in seconds) required to complete the task was considered as final score.[9] Number connection test B (NCT B) –For this, modified scale as per the local language (Hindi was used) Instead of using English Alphabets A,B, C and so on, Hindi varnmala (क, ख, ग, घ , and so on) were employed. The patient was instructed to join the circles in the following pattern: "1– क–2– ख and so on up to 13." If the patient makes a mistake, they have to stop, fix it, and then continue while the timer is still running. The time (in seconds) required to complete the task was final score.[9] Serial dotting test (SDT) –the test participant must place a central dot in the 100 circles as quickly as possible. The time (in seconds) required determine the final score.[9] Line tracing test (LTT) – The line tracing test (LTT) uses two parallel lines to create a maze. The patient was asked to trace a path inside the maze without coming into contact with or going over any of the barriers. The number of mistakes and the time (in seconds) required to finish the maze are the two outcomes that are measured.[9] Statistical mean of controls was calculated for all 5 tests individually. Individual values of cases were then calculated. For all tests except for DST, scores between +1 and -1 SD were given a score of 0, in between +1 and +2 SD were given a score of -1, between +2 and +3 SD were given a score of -2 and those beyond +3 SD were given a score of -3. Those having scores less than -1 SD were given a score of +1. For DST, scores between +1 and -1 SD were given a score of 0, in between -1 and -2 SD were given a score of -1, between -2 and -3 SD were given a score of -2 and those less than -3 SD were given a score of -3. Those having scores greater than +1 SD were given a score of +1. Sum of all scores were taken and those having a total score of less than -4 were considered having minimal hepatic encephalopathy. Further EEG was done and findings were documented. STATISTICAL ANALYSIS Data was compiled using MS-Excel and analysis was done using IBM SPSS software version 20. Categorical data was expressed as frequency and percentage whereas continuous data was expressed as mean and standard deviation. comparison of categorical data between cases and controls was done using chi square test whereas comparison of continuous data between cases and control was done using independent t test. P value of less than 0.05 was considered significant.

The present study was conducted on a total of 70 patients with cirrhosis and 70 healthy controls. Table 1- Distribution of cases and controls according to baseline variables Baseline variables Cases (n=70) Controls (n=70) P value n % n % Age (years) ≤30 5 7.1 8 11.4 0.46 31– 40 18 25.7 21 30.0 41 – 50 24 34.3 15 21.4 51– 60 17 24.3 17 24.3 ≥60 6 8.6 9 12.9 Mean±SD 45.66±10.96 44.26±12.53 Gender Male 55 78.6 54 77.1 0.84 Female 15 21.4 16 22.9 The mean age of cases with cirrhosis was 45.66±10.96 years whereas mean age of controls was 44.26±12.53 years. Majority of patients with Cirrhosis belonged to 41 to 50 years of age (34.3%). We observed a male predominance for cirrhosis with male:female ratio of 3.7:1. About 78.6% cases were males whereas 77.1% controls were males. Thus, cases and controls were comparable with respect to age and gender (p>0.05) (Table 1). Table 2- Comparison of PHES scale between cases and controls PHES Cases (n=70) Controls (n=70) P value NCT A 81.99±16.42 63.74±7.88 0.001 NCT B 119.21±25.24 94.81±13.62 0.001 DST 18.06±4.69 23.39±3.85 0.001 LDT 75.94±11.199 61.63±9.22 0.001 SDT 76.49±13.66 64.37±6.80 0.001 PHES -5.97±4.89 -0.21±1.39 0.001 We found mean NCT A to be significantly higher in cases as compared to controls (81.99±16.42 vs. 63.74±7.88; p<0.05). Similarly, mean NCT B was found to be significantly higher in cases (119.21±25.24) as compared to controls (94.81±13.62; p<0.05). However, mean DST was found to be significantly lower in cases as compared to controls (18.06±4.69 vs. 23.39±3.85; p<0.05). Mean LTT and SDT in cases with cirrhosis was 75.94±11.199 and 76.49±13.66 respectively, which was significantly higher as compared to controls (61.63±9.22 and 64.37±6.80 respectively; p<0.05). Overall, mean PHES score was -5.97±4.89 in cases whereas that in controls was -0.21±1.39 and the observed difference in mean PHES score between cases and controls was statistically significant (p<0.05) (Table 2). We observed minimal hepatic encephalopathy in significantly higher proportions of cases with cirrhosis as compared to controls (57.1% vs. 1.4%; p<0.05) (Figure 2). Table 3- Association of Minimal Hepatic encephalopathy with EEG in cases EEG MHE Absent (n=30) Present (n=40) n % n % Not Suggestive 30 47.6 33 52.4 Suggestive 0 0.0 7 100 ꭓ2 5.83 P value 0.016 EEG was suggestive of HE in 7 cases and among them, all the cases had MHE whereas out of 63 cases in which MHE was non suggestive of EEG, 52.4% cases had MHE. The observed association of MHE with EEG was statistically significant (p<0.05) (Table 3).

Minimal HE (MHE) refers to a clinically inapparent and an earliest form of hepatic encephalopathy, characterized by CNS abnormalities in the form of inattention, reduced psychomotor speed, poor visuospatial perception, delayed processing of information.[2,3] As these patients do not exhibit features of hepatic encephalopathy and standard neurologic examination are generally within normal limits.[6] Although various neuropsychological tests have been developed for assessing MHE such as computer tests (crucial flicker frequency and inhibitory control tests), psychometric evaluations, and electrophysiological analyses. However, the Psychometric Hepatic Encephalopathy Score (PHES) are most effective clinical technique for identifying MHE.[5] This test consists of battery of tests, which include Number Connection Tests (NCTs) A and B, Digit Symbol Test (DST), Serial Dotting Test (SDT), Line Tracing Test (LTT).[10,11] The present study was conducted at tertiary care centre to assess the effectiveness of PHES in detecting minimal hepatic encephalopathy in liver cirrhosis patients. We conducted this study on 70 patients with cirrhosis and 70 age and sex matched healthy controls were also included. Although minimal hepatic encephalopathy is common feature of cirrhosis, non cirrhotic patients may also experience MHE.[12] We conducted PHES battery of tests on cases with cirrhosis and healthy controls and assessed the proportions of patients with MHE. We found that mean NCT A, NCT B, LDT and SDT to be significantly higher in cases as compared to controls whereas mean DST was significantly lower in cases (p<0.05). Mean PHES score was -5.97±4.89 whereas that in controls was -0.21±1.39. Based upon these battery of tests, MHE was observed in more than half of the patients with cirrhosis (57.1%). On the other hand, minimal hepatic encephalopathy was documented in 1 (1.4%) control. As PHES score was used to detect MHE, all the battery of tests i.e. NCT A, NCT B, DST, LDT and SDT scores were significantly deranged in cases with MHE as compared to patients without MHE (p<0.05). Our study findings were supported by the findings of Duarte et al, in which the authors documented MHE in 15% cases with cirrhosis with no overt hepatic encephalopathy.[13] Further, Thanapirom et al reported mean PHES score to be significantly lower in cases with cirrhosis as compared to healthy controls and MHE was observed in 26.6% cases with cirrhosis.[10] In a study of Gairing et al, MHE was detected in 35% cases of cirrhosis based on PHES battery of tests, however, after excluding cases with overt HE, the prevalence of MHE was 29%.[14] Taneja et al observed MHE in 40.2% of the individuals in their study using PHES.[15] Tsai et al reported MHE in 29% cases if cirrhosis.[16] Kavya et al reported MHE in 62% cases of cirrhosis using PHES battery of tests and found NCT-A and DST to be more accurate for detecting MHE.[17] Kumbara et al documented MHE in 37.7% cases of cirrhosis.[18] Pessidjo Djomatcho et al documented much higher prevalence of MHE in their study in cirrhotic group (74%) with mean PHES score of −7.66 ± 5.62 whereas the mean PHES score in healthy volunteers was − 0.08 ± 1.28.[19] This could be attributed to inclusion of higher proportions of cases with decompensated cirrhosis and elderly patients. Our study had certain limitations, the sample size of study was small, as only 70 cases with cirrhosis were enrolled. Since the study was conducted as cross sectional study, both short term and long term outcome of the patients with and without MHE could not be assessed. Also, the study did not assess the follow up in patients diagnosed with MHE and the impact of specific treatments (e.g., medications) on the Outcome of patients with MHE. These Limitations suggest that while the study provides valuable insights, further research with a larger sample size, longer follow ups, and multi-centre designs is necessary to confirm the Clinical utility of Psychometric scoring.

The PHES is a validated scale for assessment of Minimal hepatic encephalopathy. Minimal hepatic encephalopathy is common in cases with cirrhosis, although it may be observed in small proportions of patients with no cirrhosis. We reported MHE in 57.1% cases with cirrhosis and 1.4% controls. PHES cannot only identify cases that are identified by EEG, but also the cases that are missed by EEG. PHES can be used as an easy Bed-side tool for diagnosing Minimal Hepatic Encephalopathy. Thus, PHES can be utilized effectively in diagnosis of MHE early and preventing the complications associated with overt hepatic encephalopathy.

1. Ferenci P. Hepatic encephalopathy. Gastroenterol Rep (Oxf). 2017 May;5(2):138-47. 2. Amodio P, Montagnese S, Gatta A, Morgan MY. Characteristics of minimal hepatic encephalopathy. Metabolic brain disease. 2004 Dec;19:253-67. 3. Das A, Dhiman RK, Saraswat VA, Verma M, Naik SR. Prevalence and natural history of subclinical hepatic encephalopathy in cirrhosis. Journal of gastroenterology and hepatology. 2001 May;16(5):531-5. 4. Stinton LM, Jayakumar S. Minimal hepatic encephalopathy. Can J Gastroenterol. 2013 Oct;27(10):572-4. 5. Weissenborn K. Diagnosis of minimal hepatic encephalopathy. Journal of clinical and experimental hepatology. 2015 Mar 1;5:S54-9. 6. Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy—definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. 2002 Mar 1;35(3):716-21. 7. Pawar VB, Surude RG, Sonthalia N, Zanwar V, Jain S, Contractor Q, Rathi PM. Minimal hepatic encephalopathy in Indians: psychometric hepatic encephalopathy score and inhibitory control test for diagnosis and rifaximin or lactulose for its reversal. Journal of Clinical and Translational Hepatology. 2019 Dec 12;7(4):304. 8. Dhiman RK, Saraswat VA, Sharma BK, Sarin SK, Chawla YK, Butterworth R, Duseja A, Aggarwal R, Amarapurkar D, Sharma P, Madan K. Minimal hepatic encephalopathy: consensus statement of a working party of the Indian National Association for Study of the Liver. Journal of Gastroenterology and Hepatology. 2010 Jun;25(6):1029-41. 9. Mumdzhiev N, Tenev RV, Radicheva MP. Psychometric hepatic encephalopathy score (PHES)–when, how, why, and why not: a guide for the unfamiliar. Gastroenterology Review/Przegląd Gastroenterologiczny. 2016;19(1). 10. Thanapirom K, Wongwandee M, Suksawatamnuay S, Thaimai P, Siripon N, Makhasen W, Treeprasertsuk S, Komolmit P. Psychometric hepatic encephalopathy score for the diagnosis of minimal hepatic encephalopathy in Thai cirrhotic patients. Journal of Clinical Medicine. 2023 Jan 8;12(2):519. 11. Li SW, Wang K, Yu YQ, Wang HB, Li YH, Xu JM. Psychometric hepatic encephalopathy score for diagnosis of minimal hepatic encephalopathy in China. World Journal of Gastroenterology: WJG. 2013 Dec 12;19(46):8745. 12. Mínguez B, García‐Pagán JC, Bosch J, Turnes J, Alonso J, Rovira A, Córdoba J. Noncirrhotic portal vein thrombosis exhibits neuropsychological and MR changes consistent with minimal hepatic encephalopathy. Hepatology. 2006 Apr;43(4):707-14. 13. Duarte-Rojo A, Estradas J, Hernández-Ramos R, Ponce-de-León S, Córdoba J, Torre A. Validation of the psychometric hepatic encephalopathy score (PHES) for identifying patients with minimal hepatic encephalopathy. Digestive diseases and sciences. 2011 Oct;56:3014-23. 14. Gairing SJ, Mangini C, Zarantonello L, Gioia S, Nielsen EJ, Danneberg S, Gabriel M, Ehrenbauer AF, Bloom PP, Ripoll C, Sultanik P. Prevalence of minimal hepatic encephalopathy in patients with liver cirrhosis: a multicenter study. Official journal of the American College of Gastroenterology| ACG. 2023 Dec 1;118(12):2191-200. 15. Taneja S, Dhiman RK, Khatri A, Goyal S, Thumbru KK, Agarwal R, Duseja A, Chawla Y. Inhibitory control test for the detection of minimal hepatic encephalopathy in patients with cirrhosis of liver. Journal of clinical and experimental hepatology. 2012 Dec 1;2(4):306-14. 16. Tsai CF, Chu CJ, Huang YH, Wang YP, Liu PY, Lin HC, Lee FY, Lu CL. Detecting minimal hepatic encephalopathy in an endemic country for hepatitis B: the role of psychometrics and serum IL-6. PloS one. 2015 Jun 3;10(6):e0128437. 17. Kavya JH, Varun MP. ROLE OF PSYCHOMETRIC HEPATIC ENCEPHALOPATHY SCORE (PHES) IN DETECTION OF MINIMAL HEPATIC ENCEPHALOPATHY IN PATIENTS WITH CIRRHOSIS OF LIVER. Int. J Sci. Res. 2023 February; 12 (2): 37-8. 18. Kumbara CI, Wibawa ID, Widiana IG. The Psychometric Hepatic Encephalopathy Score for Diagnosis of Minimal Hepatic Encephalopathy in Liver Cirrhosis Patient. The Indonesian Journal of Gastroenterology, Hepatology, and Digestive Endoscopy. 2024 May 27;25(1):40-6. 19. Pessidjo Djomatcho L, Kowo MP, Ndam AN, Njonnou SR, Kenfack GU, Andoulo FA, Bagnaka SF, Bekolo WT, Malongue A, Babagna ID, Sida MB. Normalisation of the psychometric encephalopathy score within the Cameroonian population. BMC gastroenterology. 2021 Dec;21:1-7.